DESCRIPTION (adapted from the application) Hepatitis C Virus (HCV) persists in more than 80% of those initially infected and over the course of decades causes chronic liver disease that can be associated to hepatocellular carcinoma, cryoglobulinemia and autoimmunity. Immune responses to HCV have been studied at the antibody, CD4, and CD8 levels in both the peripheral blood and the liver. Strong antibody responses are observed to all HCV proteins and both helper and cytotoxic T-cells have been isolated from each site of infection. Despite such evidence of immune recognition, the mechanisms by which HCV establishes and maintains infection are not well understood. Speculation that chronic HCV infection may arise from several different mechanisms is based on a number of observations that include evidence of immune deviation and generation of escape variants, neither of which is mutually exclusive. Type 2 cytokines have been observed in the serum of chronically infected patients and studies with peripheral blood T-cells have shown that HCV antigen stimulation often results in secretion of Type 2 cytokines. Paradoxically, studies in the liver suggest that local production of Th1-associated cytokines correlates with progressive hepatic damage. Because of many such similar findings in a variety of models, responses in the peripheral blood are often discounted as irrelevant to site-specific immune responses. Recognizing that HCV also infects peripheral blood mononuclear cells, however, it may be possible to reconcile such disparate results if it is postulated that the peripheral blood provides a source for constant re-infection of the liver and thus also, chronic viral persistence. Therefore, an understanding of peripheral immune responses to HCV is also critical to understanding viral immunopathogenesis. Our hypothesis is that the evasive mechanisms used by HCV arise from intrinsic hypermutability in T-cell epitopes encoded throughout the genome and that under host immune selection, there is an accumulation of HCV quasispecies expressing functionally tolerogenic epitopes conducive to viral persistence. We further postulate that in the evolutionary process by which such functionally tolerogenic epitopes are selected, helper T-cell responses shift towards a Th2 phenotype favoring chronic infection and creating a tolerogenic bias that specifically dampens effective anti-HCV responses. We believe that understanding the structural constraints upon helper T-cell interactions with functionally distinct HCV epitopes provides a powerful vantage point from which to study immune regulation in humans, our primary interest, and also leads to strategies for intervening in the infectious process. Our aims are to examine the relationship between viral mutation and functionally distinct helper T-cell epitopes that stimulate production of different cytokines; to determine the mechanism of IL-2 suppression in response to an immunodominant epitope within the non-structural (NS) 3 protein antigen of HCV.